The present invention relates to acylguanidine derivatives of the formula I, 
in which R1, R2, R4, R5, R6, A, m and n have the meanings indicated below, their physiologically tolerable salts and their prodrugs. The compounds of the formula I are valuable pharmaceutical active compounds. They are vitronectin receptor antagonists and inhibitors of bone resorption by osteoclasts and are suitable, for example, for the therapy and prophylaxis of diseases which are caused at least partially by an undesired extent of bone resorption, for example of osteoporosis. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as pharmaceutical active ingredients, and pharmaceutical preparations comprising them.
Human bones are subject to a constant dynamic renovation process comprising bone resorption and bone formation. These processes are controlled by types of cell specialized for these purposes. Bone resorption is based on the destruction of bone matrix by osteoclasts. The majority of bone disorders are based on a disturbed equilibrium between bone formation and bone resorption.
Osteoporosis is a disease characterized by low bone mass and enhanced bone fragility resulting in an increased risk of fractures. It results from a deficit in new bone formation versus bone resorption during the ongoing remodelling process.
Conventional osteoporosis treatment includes, for example, the administration of bisphosphonates, estrogens, estrogen/progesterone (hormone replacement therapy or HRT), estrogen agonists/antagonists (selective estrogen receptor modulators or SERMs), calcitonin, vitamin D analogues, parathyroid hormone, growth hormone secretagogues, or sodium fluoride (Jardine et al., Annual Reports in Medicinal Chemistry 1996, 31, 211).
Activated osteoclasts are polynuclear cells having a diameter of up to 400 xcexcm, which remove bone matrix Activated osteoclasts become attached to the surface of the bone matrix and secrete proteolytic enzymes and acids into the so-called xe2x80x9csealing zonexe2x80x9d, the region between their cell membrane and the bone matrix. The acidic environment and the proteases cause the destruction of the bone. The compounds of the formula I inhibit bone resorption by osteoclasts.
Studies have shown that the attachment of osteoclasts to the bones is controlled by integrin receptors on the cell surface of osteoclasts. Integrins are a superfamily of receptors which include, inter alia, the fibrinogen receptor xcex1IIbxcex23 on the blood platelets and the vitronectin receptor xcex1vxcex23. The vitronectin receptor xcex1vxcex23 is a membrane glycoprotein which is expressed on the cell surface of a number of cells such as endothelial cells, cells of the vascular smooth musculature, osteoclasts and tumor cells. The vitronectin receptor xcex1IIbxcex23, which is expressed on the osteoclast membrane, controls the process of attachment to the bones and bone resorption and thus contributes to osteoporosis. xcex1vxcex23 in this case binds to bone matrix proteins such as osteopontin, bone sialoprotein and thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).
Horton and coworkers describe RGD peptides and an anti-vitronectin receptor antibody (23C6) Which inhibit tooth destruction by osteoclasts and the migration of osteociasts (Horton et al., Exp. Cell. Res. 1991, 195, 368). In J. Cell Biol. 1990, 111, 1713, Sato et al. describe echistatin, an RGD peptide from snake venom, as a potent inhibitor of bone resorption in a tissue culture and as an inhibitor of osteoclast adhesion to the bones. Fischer et al. (Endocrinology 1993, 132, 1411) were able to show in the rat that echistatin also inhibits bone resorption in vivo.
It was furthermore shown that the vitronectin receptor xcex1vxcex23 on human cells of the vascular smooth musculature of the aorta stimulates the migration of these cells into the neointima, which finally leads to arteriosclerosis and restenosis after angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815). Yue et al. (Pharmacology Reviews and Communications 1998, 10, 9-18) showed the inhibition of neointima formation using an xcex1vxcex23 antagonist.
Brooks et al. (Cell 1994, 79, 1157) showed that antibodies against xcex1vxcex23 or xcex1vxcex23 antagonists can cause a shrinkage of tumors by inducing the apoptosis of blood vessel cells during angiogenesis. The vitronectin receptor xcex1vxcex23 is also involved in the progression of a variety of other types of cancer, and is overexpressed in malignant melanoma cells (Engleman et al., Annual Reports in Medicinal Chemistry 1996, 31, 191). The melanoma invasiveness correlated with this overexpression (Stracke et al., Encylopedia of Cancer, volume III, 1855, Academic Press, 1997; Hillis et al., Clinical Science 1996, 91, 639). Carron et al. (Cancer Res. 1998, 58, 1930) describe the inhibition of tumor growth and the inhibition of hypercalcemia of malignancy using an xcex1vxcex23 antagonist.
Cheresh et al. (Science 1995, 270, 1500) describe anti-xcex1Vxcex23 antibodies or xcex1vxcex23 antagonists which inhibit the bFGF-induced angiogenesis processes in the rat eye, a property which can be used therapeutically in the treatment of retinopathies.
Influencing of the vitronectin receptor or of the interactions in which it is involved thus offers the possibility of influencing different disease states for whose therapy and prophylaxis there continues to be a need for suitable pharmaceutical active ingredients.
The patent application WO-A-94/12181 describes substituted aromatic ring systems and WO-A-94/08577 describes substituted heterocycles as fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A-528 586 and EP-A-528 587 disclose aminoalkyl-substituted or heterocyclyl-substituted phenylalanine derivatives. WO-A-95/32710 discloses aryl derivatives as inhibitors of bone resorption by osteoclasts. WO-A-96/00574 describes benzodiazepines, and WO-A-96/00730 describes fibrinogen receptor antagonist templates, in particular benzodiazepines which are linked to a nitrogen-bearing 5-membered ring, as vitronectin receptor antagonists. WO-A-97/21726 describes agents for promoting bone formation which belong to various classes of compounds, among them tyrosine derivatives containing an unsubstituted guanidino group. Further investigations have shown that the acylguanidines of the formula I are particularly strong inhibitors of the vitronectin receptor and of bone resorption by osteoclasts.
The present invention relates to compounds of the formula I, 
in which
R1 and R2 independently of one another are hydrogen or (C1-C6)-alkyl which is unsubstituted or substituted by R3, with the proviso that R1 and R2 are not both hydrogen at the same time,
or in which the radicals R1- and R2-together are a saturated or unsaturated bivalent (C2-C9)-alkylene radical, for example the group xe2x80x94(CH2)pxe2x80x94, in which p is 2, 3, 4, 5, 6, 7, 8 or 9, which is unsubstituted or is substituted by one or more groups from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or a heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carboncarbon bond in the (C2-C9)-alkylene radical;
R3 is (C1-C8)-alkyl, (C1-C8)-alkoxy, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C4)-alkyl- halogen, trifluoromethyl, hydroxyl, nitro or amino;
R4 is hydrogen, (C1-C6)-alkyl-COxe2x80x94Oxe2x80x94(C1-C4)-alkyl- or (C1-C6)-alkyl, which is unsubstituted or is substituted by a radical from the group consisting of hydroxyl, (C1-C4)-alkoxy, (C1-C4)-alkyl-S(O)2xe2x80x94, NR7R7xe2x80x2and N+R7R7xe2x80x2R7xe2x80x3Qxe2x88x92, where R7, R7xe2x80x2 and R7xe2x80x2 independently of one another are hydrogen, (C1-C6)-alkyl, (C5-C14)-aryl or (C5-C14)-aryl-(C1-C6)-alkyl- and Qxe2x88x92 is a physiologically tolerable anion, or in which R4 is one of the radicals 
xe2x80x83in which the bonds, via which the radicals are bonded, are indicated by dashed lines;
R5 is (C1-C8)-alkyl, (C6-C14)-aryl-(C1-6)-alkyl- or (C5-C14)-heteroaryl-(C1-C5)-alkyl-, where the aryl radical or the heteroaryl radical is unsubstituted or is substituted by one, two or three radicals R3,
R6 is hydrogen, (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94, hydroxyl, (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94Oxe2x80x94 or nitro;
A is CH2, O, S or NH;
m is 1, 2or 3;
n is 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
All radicals which can occur more than once in the compounds of the formula I, for example the radicals R3, can in each case independently of one another have the meanings indicated, and they can in each case be identical or different. Similarly, all radicals of which it is said that they independently of one another can have a meaning indicated, can in each case be identical or different.
The alkyl radicals occurring in the substituents can be straight-chain or branched and can be saturated or mono-unsaturated or poly-unsaturated. This also applies if they carry substituents or occur as substituents of other radicals, for example in alkoxy radicals, alkoxycarbonyl radicals or arylalkyl radicals. The same applies to alkylene radicals (=alkanediyl radicals). Examples of suitable (C1-C9)-alkyl radicals are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, the n-isomers of these radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,4-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The bivalent radicals corresponding to the abovementioned monovalent radicals, for example methylene, ethylene, 1,3-propylene, 1,2-propylene (=1-methylethylene), 2,3-butylene (=1,2-dimethylethylene), 1,4-butylene, 1,6-hexylene, are examples of alkylene radicals.
Unsaturated alkyl radicals are, for example, alkenyl radicals such as vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl or alkynyl radicals such as ethynyl, 1-propynyl or propargyl. Unsaturated alkylene radicals, that is alkenylene radicals (=alkenediyl radicals) and alkynylene radicals (=alkynediyl radicals), can likewise be straight-chain or branched. Examples of alkenylene radicals are
vinylene or propenylene, examples of alkynylene radicals are ethynylene or propynylene.
Cycloalkyl radicals can be, for example, monocyclic, bicyclic or tricyclic. Monocyclic cycloalkyl radicals are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl or cyclododecyl, which, however, can also be substituted by, for example, (C1-C4)-alkyl. Examples of substituted cycloalkyl radicals which may be mentioned are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.
Halogen is, for example, fluorine, chlorine, bromine or iodine.
(C5-C14)-Aryl includes heterocyclic (C5-C14)-aryl radicals (=(C5-C14)-heteroaryl radicals) in which one or more of the 5 to 14 ring carbon atoms are replaced by heteroatoms such as nitrogen, oxygen or sulfur, and carbocyclic (C6-C14)-aryl radicals. Examples of carbocyclic (C5-C14)-aryl radicals are phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, where 1-naphthyl, 2-naphthyl and in particular phenyl are preferred. If not stated otherwise, aryl radicals, in particular phenyl radicals, can be unsubstituted or substituted by one or more radicals, preferably one, two or three radicals. In particular aryl radicals can be substituted by identical or different radicals from the group consisting of (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy. Generally, only up to two nitro groups can occur as substituents in the compounds of the formula I according to the invention.
In monosubstituted phenyl radicals, the substituent can be located in the 2-position, the 3-position or the 4-position, the 3- and the 4-position being preferred. If phenyl is disubstituted, the substituents can be in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. Preferably, in disubstituted phenyl radicals, the two substituents are arranged in the 3,4-position, relative to the linkage site. In trisubstituted phenyl radicals, the substituents can be in the 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position.
Beside carbocyclic systems, (C5-(C14)-aryl groups can also be monocyclic or polycyclic aromatic ring systems in which 1, 2, 3, 4 or 5 of the 5 to 14 ring carbon atoms are replaced by heteroatoms, in particular by identical or different heteroatoms from the group consisting of nitrogen, oxygen and sulfur. Examples of heterocyclic (C5-C14)-aryl groups and (C5-C14)-heteroaryl groups are 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, xcex2-carbolinyl, or benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivatives of these radicals. The heterocyclic systems can be substituted by the same substituents as the abovementioned carbocyclic aryl systems.
In the series of these heteroaryl groups, monocyclic or bicyclic aromatic ring systems having 1, 2 or 3 heteroatoms, in particular having 1 or 2 heteroatoms, from the group consisting of N, O, S, which can be unsubstituted or substituted by 1, 2 or 3 substituents from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl, are preferred. Particularly preferred here are monocyclic or bicyclic aromatic 5-membered to 1 0-membered ring systems having 1 to 3 heteroatoms, in particular having 1 or 2 heteroatoms, from the group consisting of N, O, S, which can be substituted by 1 to 2 substituents from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, phenyl, phenoxy, benzyl and benzyloxy.
If the two radicals R1- and R2- together represent a bivalent saturated or unsaturated (C2-C9)-alkylene radical, these two radicals, together with the two nitrogen atoms to which they are bonded, and the central carbon atom of the guanidino group to which these two nitrogen atoms are bonded, form a monocyclic 1,3-diazaheterocycle which is bonded to the nitrogen atom in the group (CH2)mxe2x80x94COxe2x80x94NH via its 2-position. Examples of radicals of such 1,3-diazaheterocycles which can be substituted as indicated in the (C2-C9)-alkylene radical and also on the guanidino nitrogen atom, are the 1H-imidazol-2-yl radical, the 4,5-dihydro-1H-imidazol-2-yl radical, the 1,4,5,6-tetrahydro-pyrimidin-2-yl radical or the 4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl radical. If a 5-membered to 7-membered ring is fused to a carbon-carbon bond in the (C2-C9)-alkylene radical, then the two radicals R1 and R2, together with the two nitrogen atoms to which they are bonded, and the central carbon atom of the guanidino group to which these two nitrogen atoms are bonded, form a bicyclic heterocycle which is bonded to the nitrogen atom in the group (CH2)mxe2x80x94COxe2x80x94NH and which can be substituted as indicated. The fused (or condensed) 5-membered to 7-membered ring can be saturated, mono-unsaturated or di-unsaturated or aromatic. Thus, for example, a cyclopentane ring, cyclohexane ring, cyclohexene ring, cyclohexadiene ring, cycloheptane ring or benzene ring can be condensed. Examples of radicals of such bicyclic heterocycles which can be bonded to the nitrogen atom in the group (CH2)mxe2x80x94COxe2x80x94NH are the 1,3a,4,5,6,6a-hexahydro-1,3-diazapentalen-2-yl radical, the 1H-benzimidazol-2-yl radical, the 3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl radical, the 4,5,6,7-tetrahydro-1H-benzimidazol-2-yl radical, the 4,7-dihydro-1H-benzimidazol-2-yl radical or the 1H-imidazo[4,5-b]pyridin-2-yl radical. If a condensed ring is substituted and/or if the (C2-C5)-akylene radical is substituted, they are preferably independently of one another monosubstituted or disubstituted by identical or different radicals R3. If alkyl groups representing R1 and/or R2 are substituted, they are preferably independently of one another monosubstituted or disubstituted, in particular monosubstituted, by identical or different radicals R3.
Optically active carbon atoms contained in the compounds of the formula I can independently of one another have the R configuration or the S configuration. The configurations on different centers can be identical or different. The compounds of the formula I can be present in the form of pure enantiomers or pure diastereomers or in the form of enantiomer mixtures, for example in the form of racemates, or of diastereomer mixtures. The present invention relates to both pure enantiomers and enantiomer mixtures, for example racemates, and diastereomers and diastereomer mixtures. The invention comprises mixtures of two or of more than two stereoisomers of the formula I and all ratios of the stereoisomers in the mixtures. The compounds of the formula I can optionally be present as E isomers or Z isomers. The invention relates to both pure E isomers and pure Z isomers and E/Z mixtures in all ratios. The invention also comprises all tautomeric forms of the compounds of the formula I. For example, beside the form shown in the formula I, also the form in which the acylguanidine units is present as a xe2x80x94COxe2x80x94Nxe2x95x90C(NHR1)xe2x80x94NR2R6 group, and all other forms which differ by different positions of mobile hydrogen atoms are comprised. Diastereomers, including E/Z isomers, can be separated into the individual isomers, for example, by chromatography. Racemates can be separated into the two enantiomers by customary methods, for example, by chromatography on chiral phases or by resolution. Stereochemically uniform compounds can also be obtained by employing stereochemically uniform starting compounds or by using stereoselective reactions.
Physiologically tolerable salts of the compounds of formula I are nontoxic, physiologically acceptable, in particular pharmaceutically utilizable, salts. Such salts of compounds of the formula I which contain acidic groups, for example carboxylic acid groups, are, for example, alkali metal salts or alkaline earth metal salts, such as, for example, sodium salts, potassium salts, magnesium salts and calcium salts, and also salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines, such as, for example, triethylamine, ethanolamine or tris-2-hydroxyethyl)amine. Compounds of the formula I which contain basic groups, form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds of the formula I which contain a basic group and an acidic group, for example the guanidino group and a carboxyl group, can be present as zwitterions (betaines), which are likewise included by the present invention.
The physiologically tolerable anion Qxe2x88x92, which is contained in the compounds of the formula I when R4 is an alkyl radical which is substituted by a positively charged ammonium group, is, in particular, a monovalent anion or an eqivalent of a polyvalent anion of a nontoxic, physiologically acceptable, in particular also pharmaceutically utilizable, inorganic or organic acid, for example the anion or an anion equivalent of one of the abovementioned acids suitable for the formation of acid addition salts. Qxe2x88x92 can thus be, for example, one of the anions (or an anion equivalent) chloride, sulfate, phosphate, acetate, citrate, benzoate, maleate, fumarate, tartrate, methanesulfonate or p-toluenesulfonate.
Salts of compounds of the formula I can be obtained by customary methods known to those skilled in the art, for example by combining a compound of the formula I with an inorganic or organic acid or base in a solvent or dispersant, or from other salts by cation exchange or anion exchange. The present invention also includes all salts of the compounds of the formula I which, because of low physiologically tolerability, are not directly suitable for use in pharmaceuticals, but are suitable, for example, as intermediates for carrying out other chemical modifications of the compounds of the formula I or as starting materials for the preparation of physiologically tolerable salts.
The present invention moreover includes all solvates of compounds of the formula I, for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formula I, for example esters and other prodrugs and other physiologically tolerable derivatives, as well as active metabolites of the compounds of the formula I. The invention relates in particular to prodrugs of the compounds of the formula I, which can be converted into compounds of the formula I under physiological conditions. Suitable prodrugs for the compounds of the formula I, i.e. chemically modified derivatives of the compounds of the formula I having properties which are improved in a desired manner, are known to those skilled in the art. More detailed information relating to prodrugs is found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115-130; Design of Prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 (1991) 443; Saulnier et al., Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al., Pharmaceutical Res. 10 (1993) 1350. Suitable prodrugs for the compounds of the formula I are especially ester prodrugs, for example (C1-C4)-alkyl esters, of carboxylic acid groups, in particular of the COOH group, which is present when R4 in the group COOR4 is hydrogen, and also acyl prodrugs and carbamate prodrugs of acylatable a nitrogen-containing groups such as amino groups and in particular the guanidino group. In the acyl prodrugs or carbamate prodrugs, one or more times, for example twice, a hydrogen atom located on a nitrogen atom in these groups is replaced by an acyl group or carbamate group. Suitable acyl groups and carbamate groups for the acyl prodrugs and carbamate prodrugs are, for example, the groups R10xe2x80x94COxe2x80x94 and R11Oxe2x80x94COxe2x80x94, in which R10 is hydrogen, (C1-C18)-alkyl, (C3-C14)-cycloalkyl, (C3-C14)-cycloalkyl-(C1-C8)-alkyl-, (C5-C14)-aryl, in which 1 to 5 carbon atoms can be replaced by heteroatoms such as N, O, S, or (C5-C14)-aryl-(C1-C8)-aryl-, in which 1 to 5 carbon atoms in the aryl moiety can be replaced by heteroatoms such as N, O, S, and R11 has the meanings indicated for R10 with the exception of hydrogen.
In the compounds of the formula I, the radicals R1 and R2 preferably together are a saturated or unsaturated, in particular a saturated, bivalent (C2-C5)-alkylene radical, in particular a (C2-C4)-alkylene radical, especially a (C2-C3)-alkylene radical, which is unsubstituted or is substituted by one or two identical or different radicals from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl-and oxo, where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms can be fused to a carboncarbon bond in the alkylene radical. In the compounds of the formula I, the radicals R1 and R2 are particularly preferably the group xe2x80x94(CH2)pxe2x80x94, in which p is the numbers 2, 3, 4 or 5, preferably the numbers 2, 3 or 4, particularly preferably the numbers 2 or 3, and which is unsubstituted or is substituted by one or two identical or different radicals from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-,(C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbon-carbon bond in the group xe2x80x94(CH2)pxe2x80x94.
R3 is preferably (C1-C4)-alkyl or (C1-C4)-alkoxy.
R4 is preferably hydrogen or unsubstituted or substituted (C1-C6)-alkyl, particularly preferably hydrogen or (C1-C6)-alkyl, which is unsubstituted or substituted by a radical from the group consisting of (C1-C4)-alkoxy, (C1-C4)-alkyl-S(O)2xe2x80x94 and NR7R7xe2x80x2, where R7 and R7 xe2x80x2 independently of one another are hydrogen or (C1-C4)-alkyl. R4 is very particularly preferably hydrogen or unsubstituted or substituted (C1-C4)-alkyl, especially preferably hydrogen or (C1-C4)-alkyl which is unsubstituted or substituted by a radical from the group consisting of (C1-C4)-alkoxy, (C1-C4)-alkyl-S(O)2xe2x80x94 and NR7R7xe2x80x2, where R7 xe2x80x2 and R7 independently of one another are hydrogen or (C1-C4)-alkyl.
R5 is preferably (C1-C8)-alkyl or a radical of the formula II 
in which the radicals R3 can be identical or different and can be located in any desired positions of the phenyl radical, where q is 0, 1 or 2, preferably 0 or 1, particularly preferably 0. R5 is particularly preferably (C1-C4)-alkyl or the radical of the formula II, in which q is 0 or 1, very particularly preferably R5 is the radical of the formula II, in which q is 0 or 1, i.e. an unsubstituted benzyl radical or a benzyl radical monosubstituted in the ortho-position, meta-position or par-aposition by R3.
R6 is preferably hydrogen or (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94, particularly preferably hydrogen or (C1-C4)-alkyl-Oxe2x80x94COxe2x80x94, in particular hydrogen.
A is preferably CH2 or O.
Preferred compounds of the formula I are those compounds in which one or more of the radicals have preferred meanings or one specific of the preferred meanings, all combinations of such preferred meanings being a subject of the present invention. Particularly preferred compounds of the formula I are those compounds in which
R1 and R2 together are a saturated or unsaturated bivalent (C2-C5)-alkylene radical, in particular together the group xe2x80x94(CH2)pxe2x80x94, in which p is the numbers 2, 3, 4 or 5, where the (C2-C5)-alkylene radical and the group xe2x80x94(CH2)pxe2x80x94 are unsubstituted or are substituted by a radical from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C4)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, and where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbon-carbon bond in the (C2-C5)-alkylene radical and in the group xe2x80x94(CH2)pxe2x80x94;
R3 is (C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or C1-C6)-alkyl which is unsubstituted or is substituted by a radical from the group consisting of (C1-C4)-alkoxy, C1-C4)-alkyl-S(O)2xe2x80x94 and NR7R7xe2x80x2, where R7 and R7xe2x80x2 independently of one another are hydrogen or C1-C4)-alkyl;
R5 is (C1-C8)-alkyl or a radical of the formula II 
xe2x80x83in which q is 0 or 1 and the radical R3 can be located in any desired position of the phenyl radical;
R6 is hydrogen or (C1-C6)-alkyl-Oxe2x80x94COxe2x80x94;
A is CH2 or 0;
m is 1, 2or 3;
n is 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Very particularly preferred compounds of the formula I are those compounds in which
R1 and R2 together are a saturated or unsaturated bivalent (C2-C4)-alkylene radical, in particular together the group xe2x80x94(CH2)pxe2x80x94, in which p is the numbers 2, 3 or 4, where the (C2-C4)-alkylene radical and the group xe2x80x94(CH2)pxe2x80x94 are unsubstituted or are substituted by a radical from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)aryl, (C6-C4)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C2)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, and where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carboncarbon bond in the (C2-C4)-alkylene radical and in the group xe2x80x94(CH2)pxe2x80x94;
R3 is (C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or (C1-C6)-alkyl;
R5 is (C1-C4)-alkyl or a radical of the formula II 
xe2x80x83in which q is 0 or 1 and the radical R3 can be located in any desired position of the phenyl radical;
R6 is hydrogen or (C1-C4)-alkyl-Oxe2x80x94COxe2x80x94;
A is CH2or O;
m is 1, 2or 3;
n is 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Especially preferred compounds of the formula I are those in which:
R1 and R2 together are a saturated or unsaturated bivalent (C2-C3)-alkylene radical, in particular together the group xe2x80x94(CH2)pxe2x80x94, in which p is the numbers 2 or 3, where the (C2-C3)-alkylene radical and the group xe2x80x94(CH2)pxe2x80x94 are unsubstituted or are substituted by a radical from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C4)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, and where a 5-remembered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R31, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbon-carbon bond in the (C2-C3)-alkylene radical and in the group xe2x80x94(CH2)pxe2x80x94;
R3 is (C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or (C1-C4)-alkyl;
R5 is (C1-C4)-alkyl or a radical of the formula II 
xe2x80x83in which q is 0 or 1 and the radical R3 can be located in any desired position of the phenyl radical;
R6 is hydrogen or (C1-C4)-alkyl-Oxe2x80x94COxe2x80x94;
A is CH2;
m is 1;
n is 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Especially preferred compounds of the formula I are also those in which
R1 and R2 together are a saturated or unsaturated bivalent (C2-C3)-alkylene radical, in particular together the group xe2x80x94(CH2)pxe2x80x94, in which p is the numbers 2 or 3, where the (C2-C3)-alkylene radical and the group xe2x80x94(CH2)pxe2x80x94 are unsubstituted or are substituted by a radical from the group consisting of halogen, C1-C6)-alkyl, C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C4)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl- and oxo, and where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carboncarbon bond in the (C2-C3)-alkylene radical and in the group xe2x80x94(CH2)pxe2x80x94;
R3 is (C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or (C1-C4)-alkyl;
R5 is (C1-C4)-alkyl or a radical of the formula II 
xe2x80x83in which q is 0 or 1 and the radical R3 can be located in any desired position of the phenyl radical;
R6 is hydrogen or C1-C4)-alkyl-Oxe2x80x94COxe2x80x94;
A is oxygen;
m is 1;
n is 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Especially preferred compounds of the formula I are furthermore those in which
R1 and R2 together are a saturated or unsaturated bivalent (C2-C3)-alkylene radical, in particular together the group xe2x80x94(CH2)pxe2x80x94, in which p is the numbers 2 or 3, where the (C2-C3)-alkylene radical and the group xe2x80x94(CH2)pxe2x80x94 are unsubstituted or are substituted by a radical from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl-, (C5-C14)-heteroaryl, (C5-C14)-heteroaryl-(C1-C6)-alkyl-, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6) alkyl- and oxo, and where a 5-membered to 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R3, in particular by one or two radicals R3, and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carboncarbon bond in the (C2-C3)-alkylene radical and in the group xe2x80x94(CH2)pxe2x80x94;
R3 is C1-C4)-alkyl or (C1-C4)-alkoxy;
R4 is hydrogen or C1-C4)-alkyl;
R5 is C1-C4)-alkyl or a radical of the formula II 
xe2x80x83in which q is 0 or 1 and the radical R3 can be located in any desired position of the phenyl radical;
R6 is hydrogen or C1-C4)-alkyl-Oxe2x80x94COxe2x80x94;
A is oxygen;
m is 3;
n is 0;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Particularly especially preferred compounds of the formula I are those in which
R1 and R2 together are a saturated bivalent (C2-C3)-alkylene radical which is unsubstituted, in particular together are the unsubstituted group xe2x80x94(CH2)2xe2x80x94 or the unsubstituted group xe2x80x94(CH2)3xe2x80x94;
R4 is hydrogen or (C1-C4)-alkyl;
R5 is unsubstituted benzyl;
R6 is hydrogen;
A is oxygen;
m is 3;
n is 0;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
Preferred compounds of the formula I are additionally those in which the carbon atom to which the two groups R4Oxe2x80x94COxe2x80x94 and R5OCOxe2x80x94NHxe2x80x94 are bonded has the S configuration.
The present invention also relates to processes for the preparation of the compounds of the formula I. The compounds can generally be prepared, for example in the course of a convergent synthesis, by linkage of two or more fragments which can be derived retrosynthetically from the formula I. In the preparation of the compounds of the formula I it can generally be advantageous or necessary in the course of the synthesis to introduce functional groups which could lead to undesired reactions or side reactions in the respective synthesis step, in the form of precursors which are later converted into the desired functional groups, or temporarily to block functional groups by a protective group strategy suited to the synthesis problem, which is known to those skilled in the art (Greene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991).
Thus the compounds of the formula I can be prepared, for example, by linking in a manner known per se a carboxylic acid or carboxylic acid derivative of the 
in which R4, R5, A, n and m are defined as indicated for the formula I, or alternatively functional groups can be present in the form of precursors which are later converted into the groups present in the compounds of the formula I, or functional groups are present in protected form, and in which X is a nucleophilically substitutable leaving group, with a guanidine or guanidine derivative of the formula IV 
in which R1, R2 and R6 are defined as indicated for the formula I, or alternatively functional groups can be present in the form of precursors which are later converted into the groups present in the compounds of the formula I, or functional groups are present in protected form.
The group COX in the formula III is preferably the carboxylic acid group COOH or an activated carboxylic acid derivative. X, for example, is hydroxyl or halogen, in particular chlorine or bromine, alkoxy, preferably methoxy or ethoxy, aryloxy, for example phenoxy, pentafluorophenoxy, phenylthio, methylthio, 2-pyridylthio or a radical of a nitrogen heterocycle bonded via a nitrogen atom, in particular of an azole, such as, for example, 1-imidazolyl. X can furthermore be, for example, ((C1-C4)-alkyl)xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94 or tolylsulfonyloxy and the activated acid derivative can thus be a mixed anhydride.
If X is hydroxyl, i.e. if the guanidine of the formula IV is reacted with a carboxylic acid, then the carboxylic acid is expediently first activated. The activation can be carried out, for example, with dicyclohexylcarbodiimide (DCCl) or with O-((cyano(ethoxycarbonyl)-methylen)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU; Kxc3x6nig et al., Proc. 21st Europ. Peptide Symp. 1990 (Eds. Giralt, Andreu), Escom, Leiden 1991, p. 143) or other activating reagents customary in peptide chemistry.
Beside the free guanidines of the formula IV, guanidinium salts can also be employed in the reaction with the compounds of the formula III, from which the free guanidines are then prepared in situ or in a separate step by means of a base. The reaction of an activated carboxylic acid derivative of the formula III with the guanidine (derivate) of the formula IV is preferably carried out in a manner known per se in a protic or aprotic polar, but inert, organic solvent. In this case, methanol, isopropanol, tert-butanol, dimethylformamide or tetrahydrofuran at temperatures from 0xc2x0 C. up to the boiling temperature of these solvents have proven suitable, for example, in the reaction of the methyl esters (X=methoxy) or of the ethyl esters (X=ethoxy) with the guanidines. The reactions of compounds of the type COX with salt-free guanidines are advantageously carried out in aprotic inert solvents such as dimethylformamide, tetrahydrofuran, dimethoxyethane or dioxane, if appropriate with addition of a base such as, for example, potassium tert-butoxide or sodium methoxide. However, water can also be used as a solvent in the reaction of compounds of the formula III with guanidines, for example when using a base such as sodium hdyroxide. If X is chlorine, the reaction is advantageously carried out with addition of an acid scavenger, for example of an added base or in the presence of excess guanidine (derivative) for binding the resulting hydrohalic acid. The reaction mixture is worked up and, if desired, the reaction product is then purified by the customary processes familiar to those skilled in the art.
Protective groups optionally still present in the products obtained from the compounds of the formulae III and IV are then removed by standard processes, for example tert-butyl ester groups are converted into the carboxylic acid groups by treatment with trifluoroacetic acid, benzyl groups are removed by hydrogenation or fluorenylmethoxycarbonyl groups are removed by secondary amines, and further reactions are carried out by standard processes, for example acylation reactions. If appropriate, conversion into physiologically tolerable salts or prodrugs can then be carried out by known processes.
The starting components of the formulae III and IV, which are linked to give the acylguanidine derivatives of the formula I, are commercially available or can be prepared by or analogously to processes described in the literature. The preparation of the starting components of the formula III is illustrated by way of example in the following schemes, the present invention not being restricted to these syntheses or these starting components. It does not cause any problems to those skilled in the art to carry out the modifications of the syntheses shown, which are necessary for the preparation of other compounds according to the invention.
Thus the carboxybenzaldehyde of the formula V can be reacted, for example in the presence of pyridine and piperidine, with the malonic acid ester salt of the formula VI to give the cinnamic acid derivative of the formula VII which, after hydrogenation, for example in the presence of palladium on carbon, to give the compound of the formula VII and activation of the carboxylic acid group, can be condensed with the 2,3-diaminopropionic acid derivative of the formula IX to give the compound of the formula X (Scheme 1). The condensation can be carried out, for example, in the presence of TOTU or another customary activating agent for carboxylic acids. In the formula X, Z is the benzyloxycarbonyl group, but instead of Z other groups can be present on the nitrogen atom which either only temporarily protect the amino group in the 2-position or which can also be present in the compounds of the formula I according to the invention and can remain in the molecule. Likewise, instead of the tert-butyl ester, other esters can be present which either only temporarily protect the acid group or which can also be present in the compounds of the formula I according to the invention and can remain in the molecule. Compounds analogous to the compound of the formula VII can also be obtained by other processes for the conversion of a carbonyl group into an alkene, for example by a Wittig reaction. 
The p-hydroxybenzoic acid of the formula XI can be condensed with the 2,3-diaminopropionic acid derivative of the formula IX to give the compound of the formula XII, the above explanations applying for the compound of the formula IX and the condensation. The compound of the formula XII can be alkylated with halocarboxylic acid derivatives under standard conditions, for example with the bromoacetic acid ester of the formula XIII to give the compound of the formula XIV (Scheme 2). p-Aminobenzoic acid and p-mercaptobenzoic acid can be reacted correspondingly. 
The tyrosine derivative of the formula XV can be alkylated under standard conditions with halocarboxylic acid derivatives, for example with the bromobutyric acid ester of the formula XVI to give the compound of the formula XVII (Scheme 3). In the formula XV, Z is the benzyloxycarbonyl group, but instead of Z other groups can be present on the nitrogen atom, which either only temporarily protect the amino group or which can also be present in the compounds of the formula I according to the invention and can remain in the molecule. Likewise, instead of the tert-butyl ester, other esters can be present which either only temporarily protect the acid group or which can also be present in the compounds of the formula I according to the invention and can remain in the molecule. Analogs of the compounds of the formula XVII can be prepared correspondingly or analogously to the above preparation processes. 
The compounds of the formulae X, XIV and XVII are examples of compounds of the formula III in which X is methoxy or ethoxy. These compounds and analogous compounds which are obtained from the syntheses described above containing a group which is an activated carboxylic acid derivative can be reacted directly with the compounds of the formula IV. The compounds obtained in the above syntheses, however, can also first be converted under standard conditions by cleavage of the methyl ester group or ethyl ester group or another ester group present in the position concerned in the compounds of the formulae X, XIV and XVII into the corresponding carboxylic acids, which are then reacted with the guanidines of the formula IV after in situ activation, for example with TOTU or DCCl, or after conversion into an activated carboxylic acid derivative. If, as activated acid derivatives, it is intended to prepare, for example, the carboxylic acid chlorides (formula III, X=Cl), this can be carried out, for example, using thionyl chloride. If it is intended to prepare, for example, the methyl esters (X=methoxy) from the carboxylic acids, this can be carried out by treating with gaseous hydrogen chloride in methanol. Other activated acid derivatives can be prepared in a manner known per se from the carboxylic acid chlorides or directly from the carboxylic acids on which they are based (X=OH), for example the imidazolides (X=1-imidazolyl) by treating the acids with carbonyldiimidazole (cf. Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)) or the mixed anhydrides, for example by reaction with chloroformic acid esters such as ethyl chloroformate or with tosyl chloride in the presence of amines such as triethylamine in an inert solvent. A number of suitable methods for the preparation of activated carboxylic acid derivatives are indicated with details of source literature in J. March, Advanced Organic Chemistry, Third Edition, John Wiley and Sons, 1985, p. 350.
The compounds of the formula I are valuable pharmaceutical active ingredients which are suitable, for example, for the therapy and prophylaxis of bone disorders, tumor diseases or cardiovascular disorders. The compounds of the formula I and their physiologically tolerable salts and their prodrugs can be administered to animals, preferably to mammals, and in particular to humans as pharmaceuticals for therapy or prophylaxis. They can be administered on their own, in mixtures with one another or in the form of pharmaceutical preparations which permit enteral or parenteral administration and which contain, in addition to customary pharmaceutically innocuous carriers and/or additives, an efficacious dose of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs as active constituent.
The present invention therefore also relates to the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for use as pharmaceuticals, to the use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for the production of pharmaceuticals for the therapy and prophylaxis of the diseases mentioned above or below, for example for the therapy and prophylaxis of bone disorders or tumor diseases, and also to the use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for the therapy and prophylaxis of these diseases. The present invention furthermore relates to pharmaceutical preparations which contain an efficacious amount of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs together with a customary pharmaceutically innocuous carrier.
The pharmaceuticals can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topical, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
The pharmaceutical preparations according to the invention are prepared in a manner known per se, one or more pharmaceutically inert inorganic and/or organic carriers being used in addition to the compound(s) of the formula I and/or its (their) physiologically tolerable salts and/or its (their) prodrugs. For the production of pills, tablets, coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain approximately 0.5 to 90% by weight of the compound(s) of the formula I and/or its (their) physiologically tolerable salts and/or its (their) prodrugs. The amount of the active ingredient(s) of the formula I and/or its (their) physiologically tolerable salts and/or its(their) prodrugs in the pharmaceutical preparations normally is 0.2 to 500 mg, preferably 1 to 200 mg.
In addition to the active ingredients and carriers, the pharmaceutical preparations can additionally contain one or more additives, such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings or aromatizers, thickeners, diluents, buffer substances, and also solvents or solubilizers or agents for achieving a depot effect, and also salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs. Furthermore, in addition to at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs, they can also contain one or more other therapeutically or prophylactically active ingredients.
The compounds of the formula I are antagonists of the vitronectin receptor and have, for example, the ability to inhibit the binding of osteoclasts to the bone surface and thereby bone resorption by osteoclasts. The action of the compounds of the formula I can be demonstrated, for example, in an assay in which the inhibition of the binding of vitronectin to cells which contain the vitronectin receptor is determined. Details of such an assay are given below. As vitronectin receptor antagonists, the compounds of the formula I and their physiologically tolerable salts and their prodrugs are generally suitable for the therapy and prophylaxis of diseases which are based on the interaction between vitronectin receptors and their ligands in cell-cell interaction processes or cell-matrix interaction processes, or which can be influenced by an inhibition of interactions of this type, or for their prevention, alleviation or cure an inhibition of interactions of this type is desired. As explained at the beginning, such interactions, for example, play a part in bone resorption, in angiogenesis or in the proliferation of cells of the vascular smooth musculature. The compounds of the formula I and their physiologically tolerable salts and their prodrugs are therefore suitable, for example, for the alleviation or cure of diseases which are caused at least partially by an undesired extent of bone resorption, angiogenesis or proliferation of cells of the vascular smooth musculature.
Bone diseases for whose treatment and prevention the compounds of the formula I according to the invention can be employed are especially osteoporosis, hypercalcemia, osteopenia, for example caused by metastases, dental disorders, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget""s disease. In addition, the compounds of the formula I can be used for the allevation, avoidance or therapy of bone disorders which are caused by a glucocorticoid, steroid or corticosteroid therapy or by a lack of sex hormone(s). All these disorders are characterized by bone loss, which is based on the inequilibrium between bone formation and bone destruction and which can be favorably influenced by the inhibition of bone resorption by osteoclasts. The compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs can also favorably be used as inhibitor of bone resorption, for example in the therapy or prophylaxis of osteoporosis, in combination with conventional osteoporosis treatments, for example in combination with bisphosphonates, estrogens, estrogen/progesterone, estrogen agonists/antagonists, calcitonin, vitamin D analogues, parathyroid hormone, growth hormone secretagogues, or sodium fluoride. Administration of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs and of other active ingredients effective in the treatment or prophylaxis of osteoporosis like those listed before can take place simultaneously or sequentially, in any order, and jointly or separately. For use in such a combination treatment or prophylaxis the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs and one or more other active ingredients like those listed before can together be present in a single pharmaceutical preparation, for example tablets or granules, or can be present in two or more separate pharmaceutical preparations which can be contained in a single package or in two or more separate packages. The use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs in such a combination therapy or prophylaxis and their use in the production of pharmaceuticals for such a combination therapy or prophylaxis are also covered by the present invention. The invention furthermore relates to pharmaceutical preparations which comprise efficacious amounts of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs together with at least one other active ingredient effective in the treatment. or prophylaxis of osteoporosis or in the inhibition of bone resorption like those listed before, together with a customary pharmaceutically innocuous carrier. The above explanations on pharmaceutical preparations correspondingly apply to such pharmaceutical combination preparations. Apart from use as inhibitors of bone resorption by osteoclasts, the compounds of the formula I and their physiologically tolerable salts and their prodrugs are used as inhibitors of tumor growth and tumor metastasis, as antiinflammatories, for the therapy or prophylaxis of cardiovascular disorders such as arteriosclerosis or restenosis, or for the therapy or prophylaxis of nephropathies or retinopathies, such as, for example, diabetic retinopathy. As inhibitors of tumor growth or tumor metastasis the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs can also favorably be used in combination with conventional cancer therapy. Examples of conventional cancer therapy are given in Bertino (Editor), Encyclopedia of Cancer, Academic Press, 1997. All the above statements relating to the use of the compounds of formula I in combination with conventional osteoporosis therapy like, for example, possible modes of administration and pharmaceutical combination preparations, correspondingly apply to the use of the compounds of formula I in combination with conventional cancer therapy.
When using the compounds of the formula I, the dose can vary within wide limits and, as is customary, is to be suited to the individual conditions in each individual case. It depends, for example, on the compound employed which can be physiologically active by itself or can be a prodrug that is first metabolically activated, or on the nature and severity of the disease to be treated, or on whether an acute or chronic condition is treated or whether prophylaxis is carried out. In the case of oral administration, the daily dose is in general 0.01 to 100 mg/kg, preferably 0.1 to 50 mg/kg, in particular 0.1 to 5 mg/kg, for example 0.3 to 0.5 mg/kg, to achieve effective results in an adult weighing about 75 kg (in each case in mg per kg of body weight). Also in the case of intravenous administration the daily dose is in general approximately 0.01 to 100 mg/kg, preferably 0.05 to 10 mg/kg (in each case per kg of body weight). The daily dose can be divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upwards or downwards from the daily dose indicated.
Apart from use as pharmaceutical active ingredients, the compounds of the formula I can also be used as vehicles or carriers of active ingredients in order to transport the active ingredient specifically to the site of action (=drug targeting; see, for example, Targeted Drug Delivery, R. C. Juliano, Handbook of Experimental Pharmacology, Vol. 100, Ed. Born, G. V. R. et al., Springer Verlag). The active ingredients to be transported are in particular those which can be used for the treatment of the abovementioned diseases.
The compounds of the formula I and their salts can furthermore be employed for diagnostic purposes, for example in in vitro diagnoses of cell or tissue samples, and as auxiliaries in biochemical investigations in which blocking of the vitronectin receptor or influencing of cell-cell or cell-matrix interactions is desired. They can furthermore be used as intermediates for the preparation of other compounds, in particular of other pharmaceutical active ingredients, which are obtainable from the compounds of the formula I, for example by modification or introduction of substituents or functional groups.